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General factors affecting drug metabolism: effect of physiological factors and disease 2
A selection of talks on Biochemistry
The ERK1/2 MAPK cascade
- Prof. Melanie H. Cobb
- University of Texas Southwestern Medical Center at Dallas, USA
Amino acid conjugation: mechanism and enzymology
- Dr. Kathleen Knights
- Flinders University, Australia
We will now move on to the topic of drug metabolism in inflammatory disease states which, as we will see, is applicable to a wide variety of diseases in humans.
The symptoms of inflammation were described more than two centuries ago by Celsus, tumor, rubor, calor and dolour, or, swelling, redness, heat and pain. These symptoms are the result of a local or systemic response to infection or injury designed to eliminate or control invading pathogens or to allow tissue recovery and repair following injury. But an exaggerated, inappropriate or chronic inflammatory response can be deleterious and many human diseases have an inflammatory component. Local inflammation is characterized by vasodilation, neutrophil recruitment and a cascade of pro-inflammatory cytokine and they cause node release. The triggering events of an inflammatory response are many and varied. But, in the case of infection usually result from the activation by microbial products of pattern recognition receptors such as Toll-like receptors on cells of the innate or adaptive immune systems. Physical or thermally-derived injuries initiate inflammation by activating mast cells in the tissues which release histamine and tumor necrosis factor alpha, again initiating the inflammatory cascade.
Perhaps, the first indication that inflammation could affect drug metabolism was this publication from 1953 by Samaras and Dietz. Analogous to the experiments we discussed earlier, these investigators were studying the metabolism of pentobarbital in rats by measuring the time the animals slept after a single dose of the barbiturate. They injected the animals with trypan blue, an activator of the immune system or saline. They then injected pentobarbital and measured the sleeping time. Animals treated with trypan blue slept longer than the control animals indicating that the metabolism clearance of pentobarbital had been impaired. Only sporadic additional contributions to